9-spiro-(1&#39;-substituted piperidyl-4&#39;)-4 substituted -1, 4, 8-triazabicyclo [5, 3, 0] ecane-delta7, 8-10-ones



United States Patent 3,313,819 9 SPIRO (1' SUBSTITUTED PIPERIDYL 4) 4SUBSTITUTED 1,4,8 TRIAZABICYCLO [5,3,0] DECANE-A -10-0NES Rudolf G.Griot, Florham Park, NJ., assignor to Sandoz Inc., Hanover, NJ. NoDrawing. Filed May 27, 1964, Ser. No. 370,679 9 Claims. (Cl. 260294).

The subject application is a continuation-in-part of application Ser.No. 354,431, filed on Mar. 24, 1964.

This invention is directed to spirotetrazo compounds of the formulawherein each of R and R is either a hydrogen atom (-H) or lower alkyl,e.g. methyl, ethyl, isopropyl, butyl and amyl. These compounds areprepared according to reactions (A) to (D):

A Y NH: CzHa-O R-Ni N-Cbz 00011 N (III) Cbz is carbobenzoxy;

Et is ethyl;

AcOH is acetic acid;

X is either chlorine or bromine; and

each of R and R has its above-defined meaning, except: in reactions (C)and (D) both R and R are lower alkyl. In reaction (C) a hydrogen atom asR in compound (V) is converted to a methyl group as R in compound (VI).In reaction (D) a hydrogen atom as R in compound (V) is converted to R(instead of R) in compound (VII).

/ If it is desired to produce a compound wherein R is a hydrogen atomand R is lower alkyl, the R-position is protected, as by a carbobenzoxygroup, during the alkylation (D). Thereafter the carbobenzoxy group isremoved according to reaction (B).

Compounds (I) are tranquilizers and blood pressure reducing agents. Theyare administered orally or parenterally in daily doses from 200milligrams to 400 milligrams. All acid addition salts of (I) areintermediates from which (I) may be freed.

In the examples which follow, the parts and percentages are by weightunless otherwise specified, and the temperatures are in degreescentigrade. The relationship between parts by weight and parts byvolume. is the same as that between the kilogram and the liter.

EXAMPLE 1 4-amin0-4-carb0xy-1-methyl-piperidine NH-C 0 'fi t. N112 HacN\/: saDom ca 1011 H3C I\ H or CO-NH (or H2804) COOH Reflux 22 parts of8-methyl-1,3,8-triazaspiro [4,5]dec ane-2,4-dione [Mailey, Everett A.,and Day, Allan R., J. Organic Chemistry, 22, 106 1 (1957)] in 125 partsby volume of percent sulfuric acid for twenty-four hours (oilbath 160;reaction mixture at about 130). Cool the resulting clear solution to 20,and thereafter dilute same with 250 parts by volume of water. Pass thethus diluted solution slowly through a column (twice the volume of thewater of dilution) of Dowex 50WX8.

Rinse the ion exchanger sequentially with 1000 parts by volume of waterand with 1000 parts by volume of methanol. Thereafter elute the aminoacid from the ion exchanger with 6000 parts by volume of a 5 percentsolution of ammonio (NH in methanol.

Evaporate the eluate to dryness. There are thus obtained 13 parts ofcrystalline title compound, melting point (M.P.) 286 (decomp.).

EXAMPLE 2 8-carb0benz0xy-L3,8-triazaspir0 [4,5] decane-2,4-di0ne Q o= 3Nn K HN o-=0 (NHmC 03 EtOH/HZO 3 I Heat an aqueous ethanol solution ofl-carbobenzoxy- 4-piperidone (c) [boiling point (B.P) 100/0.05millimeters (mm.); u =1.536], ammonium carbonate and potassium cyanideaccording to the procedure described by Mailey and Day, I. OrganicChemistry, 22, 1061 (1957), and separate the title spirohydantoin (D)accordingly from the resulting reaction mixture.

8 benzyl 1,3,8 triazaspiro[4,5]decane 2,4 dione (f) is prepared from1-benzyl-4-piperidone (e) according to the same procedure.

3 EXAMPLE 3 1-carb0benz0xy-4-amin0-4-carb0xy-piperidine ll HO-O Admix(d) with a 60 percent aqueous sulfuric acid solution and saponify theformer. The title compound (g) is thus obtained. Isolate (g) by passingthe saponification product through Dowex 50WX8.

1-benzyl-4-amino-4-carboxy-piperidine (h) is prepared from (f), and4-arnino-4-carboxy piperidine (j) is prepared from1,3-8-triazaspiro[4,5]decane-2,4-dione (i) according to the thisprocedure.

EXAMPLE 5 9-spir0-(1 -methylpiperidyl-4' -4-carb0benz0xy-1,4,8-triazabicyclo [5,3,0] decen-A' -IO-One Et-O- i! Reflux 0.790 part (5moles) of (b) and 1.38 parts (5 moles) ofl-carbobenzoxy-S-ethoxy-1,4-diazacycloheptene-A (III) for twenty-fourhours in 50 parts by volume of methanol. iEvaporate the solvent from thereaction product (k). Recrystallize the title compound (k), M.-P. 132 to133, from ethyl acetate. A yield of 45 percent, based on the startingweight of (b is thus obtained.

EXAMPLE 6 9-spir0-(1'-methylpiperidyl-4)-1,4,8-triazabicycl0 [5,3,0]decen-A -10-0ne Dissolve 0.630 part (1.7 moles) of (k) in 5 parts byvolume of concentrated acetic acid. At 20 admix with the resultingsolution for 4 hours 20 parts by volume of a 27 percent solution ofhydrogen bromide in concentrated acetic acid. Filter the thus-formedcrystalline pre- 4 cipitate. Dry said precipitate, M.P. 305 to 306(dec.), in a high vacuum. This precipitate (0.450 part) is thetrihydrobromide of the title compound (1) and is very hygroscopic.

The free base (1), MP. 805 to 82.5", is prepared according to knownprocedures from the trihydrobromide, i.e. by admixture with one and ahalf equivalents of potassium carbonate. All acid addition salts(according to this invention), e.g. the dimaleinate of (1), M.P. 165 to166, are similarly converted into their corresponding free bases.

EXAMPLE 7 9-sp iro- (1 '-methylp ip eridy l-4' -4-methyl-1,4,8-triazabicycl0 [5,3,0] decen-A' -I O-one @gif Dissolve 8.2 part sof(1) in 6 parts of percent formic acid, and admix the resulting solutionwith 4.05 parts of 36 percent (aq.) formaldehyde (Eschweiler-Clarkeprocedure) Maintain the product on a boiling-water bath for four hours.Thereafter add an excess of 2 N hydrochloric acid to the resultant, andthen evaporate in vacuo to dryness.

Add sufiicient aqueous potassium carbonate to the residue to make samealkaline, and extract the thus-produced base with chloroform. Evaporatethe solvent from the chloroform extract.

To prepare the trimethanesulfonate, M.P. 224 to 225, of the titlecompound, admix the residue from the chloroform extract with amethanolic solution of methanesulfonic acid (three moles ofmethanesulfonic acid per mole of title compound). Add diethylether tothe resultant to orystallize the trimethanesulfonate, which ishygroscopic. Recrystallize said trimethanesulfonate frommethanol/diethylether.

To prepare the dimaleinate, M.P. 98 to 100, of the title compound, admixthe residue from the chloroform extract with a methanolic solution ofmaleic acid (two moles of maleic acid per mole of title compound). Adddiethylether to the result-ant to crystallize the 'dimaleina-te, whichis hygroscopic. Recrystallize said dimaleinate frommethanol/diethylether.

What is claimed is: a

1. A member selected from the group consisting of a compound of theformula wherein each of R and R is a member selected from the groupconsisting of a hydrogen atom and lower alkyl, and acid addition saltsthereof.

2. A compound of the formula wherein m is a positive whole number of atmost 6.

3. A compound of the formula wherein n is a positive whole number of atmost 6.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA